The main objectives of this research proposal are to continue our studies on the hormonal regulation of organ function and on the mode of hormone action at the cellular level. The chosen approach is one of diversification. Rat pituitary and liver tissue, and human fibroblasts will be used to correlate the binding of thyroid hormone to nuclear receptors with the expression of hormone action as determined by the selective induction of protein synthesis and of their messengers RNA. A similar experimental approach will be used to study the mode of action of estrogens. Changes in pituitary growth hormone (GH), and liver and fibroblasts malic enzyme will serve as a model for the study of thyroid hormone action, while changes in pituitary prolactin (PRL) for the study of the mode of action of estrogens. Since both thyroid hormone and estrogen bind to nuclear receptors, similarities in their mode of action will be sought as well as differences in specificity related to tissue, cell type and synthetic processes under their control. Investigations will be carried out in vitro and in vivo in order to differentiate between direct and indirect effect of the hormones. Possible effect of hromones on the processing of nuclear precursors to cytoplasmic mRNA will be studied. Studies will be applied to fibroblasts derived from patients with resistance to the action of thyroid hormone in an attempt to elucidate this inherited defect and to verify conclusions drawn from animal studies. Factors responsible for the lag in endogenous translation of newly accumulated PRL mRNA during the primary stimulation with estrogen will be studied. particular attention will be given to hormonal dose, period of hormone withdrawal, influence of the hypothalamus, pituitary cell division and cell differentiation. Pituitary cell differentiation during fetal life will also be studied by determining the sequence of appearance of GH and PRL mRNA and the synthesis of these hormones in situ. An attempt will be made to determine whether the hypothalamus plays a role in the early differentiation of pituitary cells. Changes in the concentration of TRH in pancreatic islets and in the retina will be correlated to their respective secretory and photoreceptive functions.